Enteroendocrine disruption by foodborne toxins. Many toxic chemicals and drugs elicit, upon consumption, a gastrointestinal response associated with two major pathophysiologic effects, anorexia and emesis. A major underlying mechanism for this response is the aberrant activation of enteroendocrine cells (EEC) resulting in the secretion of hormones that act via the brain to elicit food refusal and vomiting. Surprisingly little is known about the early upstream events that initiate these two responses with regard to 1) identities of specific toxin chemosensors, 2) intracellular signaling mechanisms, 3) specific contributions of different EEC lineages, and 4) the role of the diverse hormones secreted by those lineages. To address these research gaps, we are modeling enteroendocrine disruption using deoxynivalenol (DON) - a foodborne mycotoxin with global public health significance. We have recently discovered that DON induces in vitro and in vivo the release of at least four gut hormones that 1) are consistent with its potent anorectic and emetic effects and 2) implicate the involvement of at least three EEC lineages. Preliminary studies further suggest that G-protein coupled calcium-sensitive receptor (CaSR) and transient receptor potential A1 channel (TRPA1) cooperate to mediate DON-induced increase in intracellular calcium concentration ([Ca2+]i) and trigger hormone release by EEC. We are now testing the hypothesis that DON-induced anorexia and emesis result from CaSR- mediated hormone secretion by gut EEC. The expected outcome of this work is that once it is known how EECs sense DON and structurally related mycotoxins and subsequently initiate anorexia and vomiting, it will improve our ability to predict, quantify, classify and counter similar effects by other enteroendocrine disruptors found in food and the environment. Finally, it will offer platforms to screen novel functional food components and drugs which might block these toxic pathways.

Molecular mechanisms of trichothecene mycotoxin immunotoxicity. Consumption of trichothecene mycotoxins such as DON not only induces anorexia and emesis, but aberrant cytokine expression in both the gut and systemic immune compartments. Employing pharmacologic (eg receptor antagonists in vitro and in vivo) and genetic (eg KO mice, siRNA knockdown, antisense cell lines) strategies, we have demonstrated that DON activates intracellular kinase activation in mononuclear phagocytes via a unique ribotoxic stress response. This involves ribosomal binding and activation of the ribosomal-associated kinases PKR and Hck that mediate expression of an array of protein kinases including AKT, p38 and ERK leading to increased proinflammatory gene mRNA stabilization and transcription. A second key aspect of this work has been to ascertain how aberrant IL-6 expression from chronic DON exposure drives hyperproduction of immunoglobulin A (IgA) both at intestinal and extra-intestinal sites leading to tissue injury and how this effect is mitigated by consumption of dietary lipids, specifically, n-3 fatty poly unsaturated fatty acids.

n-3 polyunsaturated fatty acid suppression of environmentally-induced autoimmune disease. The prevalence of autoimmune diseases is markedly impacted by environmental factors (eg. toxicant exposures) and lifestyle choices (eg. diet). Notably, the risk of developing systemic lupus erythematosus (lupus), a prototypical autoimmune disease affecting 300,000 Americans and often associated with glomerulonephritis and kidney failure, is increased by occupational exposure (eg. Fracking, mining, construction, custodial and manufacturing industries) to silica. Research studies reveal that consumption of n-3 polyunsaturated fatty acids (PUFAs) found in fish oil holds promise for preventing and ameliorating chronic inflammatory diseases including autoimmune nephritis. We are currently testing the hypothesis that consumption of n-3 PUFAs will suppress silica-accelerated nephritis in lupus-prone mice and that this will correspond with decreased leukocyte recruitment and inflammation-associated gene expression in the kidney. This research will have a positive impact because it will be an initial step in the path to predicting how n-3 PUFA consumption or other nutritional strategies that might prevent or ameliorate acceleration of autoimmunity by silica and other toxicants. Availability of such preventative and ameliorative strategies would enable individuals who are occupationally exposed to silica to 1) reduce their risk for developing lupus and other autoimmune disease and 2) delay progression of existing autoimmunity by increasing n-3 PUFA consumption via diet and/or supplementation. Furthermore, n-3 PUFA chemoprevention and chemointervention might similarly be applied to workers who are at increased risk of autoimmunity from exposures to toxicants such as asbestos, heavy metals, trichloroethylene, and pesticides.

PUBLICATIONS:

To view our citations, follow this Pubmed link to Dr. Pestka’s papers. A recent Web of Science Citation Report indicates his h-index is 51. We have published over 270 articles in several journals including Toxicological Sciences, Toxicology and Applied Pharmacology, Toxicology, Journal of Nutrition, Journal of Nutritional Biochemistry and Journal of Food Protection. Dr. Pestka ranks first in the number of Papers among 9,727 authors in mycotoxin field (read more)